tbuckley/cabot-search huggingface dataset:
Donor Lymphocyte Infusion and Molecular Monitoring for Relapsed Myelofibrosis After Hematopoietic Cell Transplantation
Authors: Nico Gagelmann, Christine Wolschke, Anita Badbaran, Dietlinde Janson, Carolina Berger, Evgeny Klyuchnikov, Francis Ayuk, Boris Fehse, Nicolaus Kröger
Journal: HemaSphere (2023)

Hematopoietic cell transplantation (HCT) is a curative approach for myelofibrosis patients, but relapse is a major cause of treatment failure. We investigated the effect of donor lymphocyte infusion (DLI) in 37 patients with molecular (n = 17) or hematological relapse (n = 20) after HCT. Patients received median of 2 (range, 1-5) cumulative DLI (total of 91 infusions). Median starting dose was 1 × 106 cells/kg, escalated by half-log ≥6 weeks if no response nor graft-versus-host disease (GvHD) occurred. Median time to first DLI was 40 weeks for molecular relapse versus 145 weeks for hematological relapse. Overall molecular complete response (mCR) at any time was 73% (n = 27) and was significantly higher for initial molecular relapse (88%) versus hematological relapse (60%; P = 0.05). The 6-year overall survival was 77% versus 32% (P = 0.03). Acute GvHD 2-4 occurred in 22% and half of the patients achieved mCR without any GvHD. All patients who relapsed from mCR achieved after first DLI could be salvaged with subsequent DLI, showing long-term survival. No second HCT was needed for molecular relapse versus 6 for hematological relapse. This comprehensive and largest study to date suggests molecular monitoring together with DLI as standard of care and a crucial approach to achieve excellent outcomes in relapsed myelofibrosis.
Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial
Authors: John F. Seymour, John C. Byrd, Paolo Ghia, Arnon P. Kater, Asher Chanan-Khan, Richard R. Furman, Susan O’Brien, Jennifer R. Brown, Talha Munir, Anthony Mato, Stephan Stilgenbauer, Naghmana Bajwa, Paulo Miranda, Kara Higgins, Ellie John, Marianne de Borja, Wojciech Jurczak, Jennifer A. Woyach
Journal: Blood (2023)
Carbohydrate ligand engagement with CD11b enhances differentiation of tumor-associated myeloid cells for immunotherapy of solid cancers
Authors: Veronique Roche, Victor Sandoval, Claire Wolford, Zachary Senders, Julian Anthony Kim, Susan Pereira Ribeiro, Alex Yicheng Huang, Rafick-Pierre Sekaly, Joshua Lyons, Mei Zhang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Efforts to modulate the function of tumor-associated myeloid cell are underway to overcome the challenges in immunotherapy and find a cure. One potential therapeutic target is integrin CD11b, which can be used to modulate the myeloid-derived cells and induce tumor-reactive T-cell responses. However, CD11b can bind to multiple different ligands, leading to various myeloid cell functions such as adhesion, migration, phagocytosis, and proliferation. This has created a major challenge in understanding how CD11b converts the differences in the receptor-ligand binding into subsequent signaling responses and using this information for therapeutic development. Methods This study aimed to investigate the antitumor effect of a carbohydrate ligand, named BG34-200, which modulates the CD11b + cells. We have applied peptide microarrays, multiparameter FACS (fluorescence-activated cell analysis) analysis, cellular/molecular immunological technology, advanced microscopic imaging, and transgenic mouse models of solid cancers, to study the interaction between BG34-200 carbohydrate ligand and CD11b protein and the resulting immunological changes in the context of solid cancers, including osteosarcoma, advanced melanoma, and pancreatic ductal adenocarcinoma (PDAC). Results Our results show that BG34-200 can bind directly to the activated CD11b on its I (or A) domain, at previously unreported peptide residues, in a multisite and multivalent manner. This engagement significantly impacts the biological function of tumor-associated inflammatory monocytes (TAIMs) in osteosarcoma, advanced melanoma, and PDAC backgrounds. Importantly, we observed that the BG34-200-CD11b engagement triggered endocytosis of the binding complexes in TAIMs, which induced intracellular F-actin cytoskeletal rearrangement, effective phagocytosis, and intrinsic ICAM-1 (intercellular adhesion molecule I) clustering. These structural biological changes resulted in the differentiation in TAIMs into monocyte-derived dendritic cells, which play a crucial role in T-cell activation in the tumor microenvironment. Conclusions Our research has advanced the current understanding of the molecular basis of CD11b activation in solid cancers, revealing how it converts the differences in BG34 carbohydrate ligands into immune signaling responses. These findings could pave the way for the development of safe and novel BG34-200-based therapies that modulate myeloid-derived cell functions, thereby enhancing immunotherapy for solid cancers.
Evaluating the relationship between community water and sanitation access and the global burden of antibiotic resistance: an ecological study
Authors: Erica R Fuhrmeister, Abigail P Harvey, Maya L Nadimpalli, Karin Gallandat, Argaw Ambelu, Benjamin F Arnold, Joe Brown, Oliver Cumming, Ashlee M Earl, Gagandeep Kang, Samuel Kariuki, Karen Levy, Chris E Pinto Jimenez, Jenna M Swarthout, Gabriel Trueba, Pablo Tsukayama, Colin J Worby, Amy J Pickering
Journal: The Lancet Microbe (2023)

BackgroundAntibiotic resistance is a leading cause of death, with the highest burden occurring in low-resource settings. There is little evidence on the potential for water, sanitation, and hygiene (WASH) access to reduce antibiotic resistance in humans. We aimed to determine the relationship between the burden of antibiotic resistance in humans and community access to drinking water and sanitation.MethodsIn this ecological study, we linked publicly available, geospatially tagged human faecal metagenomes (from the US National Center for Biotechnology Information Sequence Read Archive) with georeferenced household survey datasets that reported access to drinking water sources and sanitation facility types. We used generalised linear models with robust SEs to estimate the relationship between the abundance of antibiotic resistance genes (ARGs) in human faecal metagenomes and community-level coverage of improved drinking water and sanitation within a defined radii of faecal metagenome coordinates.FindingsWe identified 1589 metagenomes from 26 countries. The mean abundance of ARGs, in units of log10 ARG fragments per kilobase per million mapped reads classified as bacteria, was highest in Africa compared with Europe (p=0·014), North America (p=0·0032), and the Western Pacific (p=0·011), and second highest in South-East Asia compared with Europe (p=0·047) and North America (p=0·014). Increased access to improved water and sanitation was associated with lower ARG abundance (effect estimate –0·22, [95% CI –0·39 to –0·05]) and the association was stronger in urban (–0·32 [–0·63 to 0·00]) than in rural (–0·16 [–0·38 to 0·07]) areas.InterpretationAlthough additional studies to investigate causal effects are needed, increasing access to water and sanitation could be an effective strategy to curb the proliferation of antibiotic resistance in low-income and middle-income countries.FundingBill & Melinda Gates Foundation.
BMAL1 regulates cell cycle progression and angiogenesis of endothelial cells
Authors: Inna Rabinovich-Nikitin, Lorrie A Kirshenbaum
Journal: Cardiovascular Research (2023)

Figure 1 Scheme depicts BMAL1 regulation of cell-cycle, angiogenesis, and tumorigenesis in EC.Inhibition of BMAL1 in EC impairs promoter activity and gene transcription of the cell cycle regulators, Ccna1, and Cdk1 which promotes G1 exit and cell cycle arrest.This suppresses endothelial-driven angiogenesis and tumour formation.
Cardiac lipid metabolism, mitochondrial function, and heart failure
Authors: Lorenzo Da Dalt, Ainara G Cabodevilla, Ira J Goldberg, Giuseppe Danilo Norata
Journal: Cardiovascular Research (2023)

A fine balance between uptake, storage, and the use of high energy fuels, like lipids, is crucial in the homeostasis of different metabolic tissues. Nowhere is this balance more important and more precarious than in the heart. This highly energy-demanding muscle normally oxidizes almost all the available substrates to generate energy, with fatty acids being the preferred source under physiological conditions. In patients with cardiomyopathies and heart failure, changes in the main energetic substrate are observed; these hearts often prefer to utilize glucose rather than oxidizing fatty acids. An imbalance between uptake and oxidation of fatty acid can result in cellular lipid accumulation and cytotoxicity. In this review, we will focus on the sources and uptake pathways used to direct fatty acids to cardiomyocytes. We will then discuss the intracellular machinery used to either store or oxidize these lipids and explain how disruptions in homeostasis can lead to mitochondrial dysfunction and heart failure. Moreover, we will also discuss the role of cholesterol accumulation in cardiomyocytes. Our discussion will attempt to weave in vitro experiments and in vivo data from mice and humans and use several human diseases to illustrate metabolism gone haywire as a cause of or accomplice to cardiac dysfunction.
Health Research in the Wake of Disasters: Challenges and Opportunities for Sensor Science
Authors: John Volckens, Erin N. Haynes, Sharon P. Croisant, Yuxia Cui, Nicole A. Errett, Heather F. Henry, Jennifer A. Horney, Richard K. Kwok, Sheryl Magzamen, Ana G. Rappold, Lingamanaidu Ravichandran, Les Reinlib, Patrick H. Ryan, Daniel T. Shaughnessy
Journal: Environmental Health Perspectives (2023)

Background: Disaster events adversely affect the health of millions of individuals each year. They create exposure to physical, chemical, biological, and psychosocial hazards while simultaneously exploiting community and individual-level vulnerabilities that allow such exposures to exert harm. Since 2013, the National Institute of Environmental Health Sciences (NIEHS) has led the development of the Disaster Research Response (DR2) program and infrastructure; however, research exploring the nature and effects of disasters on human health is lacking. One reason for this research gap is the challenge of developing and deploying cost-effective sensors for exposure assessment during disaster events. Objectives: The objective of this commentary is to synergize the consensus findings and recommendations from a panel of experts on sensor science in support of DR2. Methods: The NIEHS convened the workshop, "Getting Smart about Sensors for Disaster Response Research" on 28 and 29 July 2021 to discuss current gaps and recommendations for moving the field forward. The workshop invited full discussion from multiple viewpoints, with the goal of identifying recommendations and opportunities for further development of this area of research. The panel of experts included leaders in engineering, epidemiology, social and physical sciences, and community engagement, many of whom had firsthand experience with DR2. Discussion: The primary finding of this workshop is that exposure science in support of DR2 is severely lacking. We highlight unique barriers to DR2, such as the need for time-sensitive exposure data, the chaos and logistical challenges that ensue from a disaster event, and the lack of a robust market for sensor technologies in support of environmental health science. We highlight a need for sensor technologies that are more scalable, reliable, and versatile than those currently available to the research community. We also recommend that the environmental health community renew efforts in support of DR2 facilitation, collaboration, and preparedness. https://doi.org/10.1289/EHP12270
Antibody–drug conjugates: Recent advances in payloads
Authors: Zhijia Wang, Hanxuan Li, Lantu Gou, Wei Li, Yuxi Wang
Journal: Acta Pharmaceutica Sinica B (2023)

Antibody‒drug conjugates (ADCs), which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing, show great clinical therapeutic value. The ADCs' payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field. An ideal ADC payload should possess sufficient toxicity, low immunogenicity, high stability, and modifiable functional groups. Common ADC payloads include tubulin inhibitors and DNA damaging agents, with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development. However, due to clinical limitations of traditional ADC payloads, such as inadequate efficacy and the development of acquired drug resistance, novel highly efficient payloads with diverse targets and reduced side effects are being developed. This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies, co-crystal structures, and designing strategies, and further discusses the future research directions of ADC payloads. This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy, low toxicity, adequate stability, and abilities to overcome drug resistance.
Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment
Authors: Jonathan M.J. Derry, Connor Burns, Jason P. Frazier, Emily Beirne, Marc Grenley, Christopher C. DuFort, Emily Killingbeck, Michael Leon, Claire Williams, Mark Gregory, Jeffrey Houlton, Daniel Clayburgh, Paul Swiecicki, Dennis Huszar, Allison Berger, Richard A. Klinghoffer
Journal: Clinical Cancer Research (2023)

Cancer drug development is currently limited by a paradigm of preclinical evaluation that does not adequately recapitulate the complexity of the intact human tumor microenvironment (TME). To overcome this, we combined trackable intratumor microdosing (CIVO) with spatial biology readouts to directly assess drug effects in patient tumors in situ.In a first-of-its-kind phase 0 clinical trial, we explored the effects of an investigational stage SUMOylation-activating enzyme (SAE) inhibitor, subasumstat (TAK-981) in 12 patients with head and neck carcinoma (HNC). Patients scheduled for tumor resection received percutaneous intratumor injections of subasumstat and vehicle control 1 to 4 days before surgery, resulting in spatially localized and graded regions of drug exposure (∼1,000-2,000 μm in diameter). Drug-exposed (n = 214) and unexposed regions (n = 140) were compared by GeoMx Digital Spatial Profiler, with evaluation at single-cell resolution in a subset of these by CosMx Spatial Molecular Imager.Localized regions of subasumstat exposure revealed SUMO pathway inhibition, elevation of type I IFN response, and inhibition of cell cycle across all tumor samples. Single-cell analysis by CosMx demonstrated cell-cycle inhibition specific to the tumor epithelium, and IFN pathway induction commensurate with a TME shift from immune-suppressive to immune-permissive.Pairing CIVO with spatial profiling enabled detailed investigation of response to subasumstat across a diverse sampling of native and intact TME. We demonstrate that drug mechanism of action can be directly evaluated in a spatially precise manner in the most translationally relevant setting: an in situ human tumor.
Epigenetic modification of m6A regulator proteins in cancer
Authors: Yumin Wang, Yan Wang, Harsh Patel, Jichao Chen, Jinhua Wang, Zhe-Sheng Chen, Hongquan Wang
Journal: Molecular Cancer (2023)

Divergent N6-methyladenosine (m6A) modifications are dynamic and reversible posttranscriptional RNA modifications that are mediated by m6A regulators or m6A RNA methylation regulators, i.e., methyltransferases ("writers"), demethylases ("erasers"), and m6A-binding proteins ("readers"). Aberrant m6A modifications are associated with cancer occurrence, development, progression, and prognosis. Numerous studies have established that aberrant m6A regulators function as either tumor suppressors or oncogenes in multiple tumor types. However, the functions and mechanisms of m6A regulators in cancer remain largely elusive and should be explored. Emerging studies suggest that m6A regulators can be modulated by epigenetic modifications, namely, ubiquitination, SUMOylation, acetylation, methylation, phosphorylation, O-GlcNAcylation, ISGylation, and lactylation or via noncoding RNA action, in cancer. This review summarizes the current roles of m6A regulators in cancer. The roles and mechanisms for epigenetic modification of m6A regulators in cancer genesis are segregated. The review will improve the understanding of the epigenetic regulatory mechanisms of m6A regulators.
Recent Advances on Social Determinants of Mental Health: Looking Fast Forward
Authors: Margarita Alegría, Kiara Alvarez, Michelle Cheng, Irene Falgas-Bague
Journal: American Journal of Psychiatry (2023)

The fields of psychiatry and mental health are increasingly recognizing the importance of social determinants of health (SDOH) and their impact on mental health outcomes. In this overview, the authors discuss the recent research, from the past 5 years, on advances made in SDOH work. SDOH frameworks and theories have expanded to include more social conditions, from traumas associated with immigration to psychosocial and community strengths, that impact mental health and well-being. Research has consistently shown the pervasive deleterious impacts of inequitable social conditions (e.g., food insecurity, housing instability) on minoritized populations’ physical and mental health. Social systems of oppression (e.g., racism, minoritization) have also been shown to confer higher risk for psychiatric and mental disorders. The COVID-19 pandemic illuminated the inequitable impact of the social determinants of health outcomes. More efforts have been made in recent years to intervene on the social determinants through interventions at the individual, community, and policy levels, which have shown promise in improving mental health outcomes in marginalized populations. However, major gaps remain. Attention should be paid to developing guiding frameworks that incorporate equity and antiracism when designing SDOH interventions and improving methodological approaches for evaluating these interventions. In addition, structural-level and policy-level SDOH efforts are critical for making long-lasting and impactful advances toward mental health equity.
NHS workforce plan—less operational, more a blueprint for the future
Authors: Alison Leary
Journal: BMJ (2023)

NHS workforce plan-less operational, more a blueprint for the future Resolving NHS workforce issues requires the NHS to see workers as an asset, not simply a resource, writes Alison Leary Alison Leary professor of healthcare and workforce modelling 1The long awaited workforce plan is finally with us.It's hefty, at 151 pages long, and less of an operational plan and more of a blueprint for the future.
Clonotype definitions for immunogenetic studies: proposals from the EuroClonality NGS Working Group
Authors: Electra Sofou, Elisavet Vlachonikola, Laura Zaragoza-Infante, Monika Brüggemann, Nikos Darzentas, Patricia J. T. A. Groenen, Michael Hummel, Elizabeth A. Macintyre, Fotis Psomopoulos, Frederic Davi, Anton W. Langerak, Kostas Stamatopoulos
Journal: Leukemia (2023)
177Lu-DOTA-IBA Therapy in Prostate Cancer With Bone Metastases
Authors: Hongmei Li, Tingting Xu, Qingchu Hua, Li Wang, Yue Chen
Journal: Clinical Nuclear Medicine (2023)

Abstract Bone is the most common metastatic site in patients with prostate cancer. 177 Lu-DOTA-ibandronic acid ( 177 Lu-DOTA-IBA) is a new therapeutic radiopharmaceutical targeting bone metastasis. We report a case of refractory bone pain due to bone metastasis, who demonstrated an excellent therapy response after 3 cycles of 177 Lu-DOTA-IBA therapy. In addition, the patient did not have any observable adverse reactions. 177 Lu-DOTA-IBA may be a promising radiopharmaceutical for the treatment of bone metastasis.
TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation
Authors: Andrea C. Pichler, Nadège Carrié, Marine Cuisinier, Samira Ghazali, Allison Voisin, Pierre-Paul Axisa, Marie Tosolini, Céline Mazzotti, Dominic P. Golec, Sabrina Maheo, Laura do Souto, Rüçhan Ekren, Eve Blanquart, Lea Lemaitre, Virginie Feliu, Marie-Véronique Joubert, Jennifer L. Cannons, Camille Guillerey, Hervé Avet-Loiseau, Tania H. Watts, Benoit L. Salomon, Olivier Joffre, Yenkel Grinberg-Bleyer, Pamela L. Schwartzberg, Liliana E. Lucca, Ludovic Martinet
Journal: Immunity (2023)

CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immune surveillance remain unresolved. Using T cell-specific deletion and agonist antibodies, we found that CD137 modulates tumor infiltration of CD8+-exhausted T (Tex) cells expressing PD1, Lag-3, and Tim-3 inhibitory receptors. T cell-intrinsic, TCR-independent CD137 signaling stimulated the proliferation and the terminal differentiation of Tex precursor cells through a mechanism involving the RelA and cRel canonical NF-κB subunits and Tox-dependent chromatin remodeling. While Tex cell accumulation induced by prophylactic CD137 agonists favored tumor growth, anti-PD1 efficacy was improved with subsequent CD137 stimulation in pre-clinical mouse models. Better understanding of T cell exhaustion has crucial implications for the treatment of cancer and infectious diseases. Our results identify CD137 as a critical regulator of Tex cell expansion and differentiation that holds potential for broad therapeutic applications.
M1 macrophage‐derived exosomes promote autoimmune liver injury by transferring long noncoding RNA H19 to hepatocytes
Authors: Yongting Zhang, Liang Hong, Xuehui Li, Yuyu Li, Xujun Zhang, Jingjing Jiang, Fan Shi, Hongyan Diao
Journal: MedComm (2023)

Exosomes mediate intercellular communication by transmitting active molecules. The function of long noncoding RNA (lncRNA) H19 in autoimmune liver injury is unclear. Concanavalin A (ConA)-induced liver injury is well-characterized immune-mediated hepatitis. Here, we showed that lncRNA H19 expression was increased in the liver after ConA treatment, accompanied by increased exosome secretion. Moreover, injection of AAV-H19 aggravated ConA-induced hepatitis, with an increase in hepatocyte apoptosis. However, GW4869, an exosome inhibitor, alleviated ConA-induced liver injury and inhibited the upregulation of lncRNA H19. Intriguingly, lncRNA H19 expression in the liver was significantly downregulated, after macrophage depletion. Importantly, the lncRNA H19 was primarily expressed in type I macrophage (M1) and encapsulated in M1-derived exosomes. Furthermore, H19 was transported from M1 to hepatocytes via exosomes, and exosomal H19 dramatically induced hepatocytes apoptosis both in vitro and vivo. Mechanistically, H19 upregulated the transcription of hypoxia-inducible factor-1 alpha (HIF-1α), which accumulated in the cytoplasm and mediated hepatocyte apoptosis by upregulating p53. M1-derived exosomal lncRNA H19 plays a pivotal role in ConA-induced hepatitis through the HIF-1α-p53 signaling pathway. These findings identify M1 macrophage-derived exosomal H19 as a novel target for the treatment of autoimmune liver diseases.